The overall goal of this Program Project proposal is to support multidisciplinary research in the development of safe AIDS vaccine that would induce protective systemic and mucosal immune responses. To achieve these goals, we propose to design novel the newly developed virus-Iike particle (VLP) mucosal and systemic delivery system with incorporated novel consensus antigens to induce broadly cross-reactive immune responses including neutralizing antibodies in sera and external secretions. The proposed studies will be performed by investigators with established collaborative ties and mutually complementary expertise in HIV/SIV virology and molecular genetics, antigen-delivery systems, evaluation of humoral and cellular responses in the systemic and mucosal compartments of the immune system of humans and animals, and production and evaluation of immunogens for human use. The proposal consists of four inter-related projects and three Core facilities: Project 1: An Evolutionary Approach to Vaccine Strain Selection (P.I. -B.H. Hahn, UAB);Project 2: Enhancement of Virus-Iike Particle Immunogenicity (P.I. -R.W. Compans, Emory University);Project 3: Novel Technologies for Measuring AIDS Virus-specific CTL in Nonhuman Primates (P.I. -N.L. Letvin, Harvard Medical School);and Project 4: Mucosal and Systemic Responses in HIV Vaccines (P.I. -J. Mestecky, UAB). The three Core facilities include: Core A -Administrative (Director, J. Mestecky, UAB;Co-Director, B.H. Hahn, UAB;and M. Crenshaw, Project Coordinator);Core B- Nonhuman Primate (P.I. -P.N. Fultz, UAB);and Core C -Antigen Production and Vaccine Manufacturing (P.I.s -Dr. R.W. Compans, Emory University, and Dr. R.A. Robinson, Novavax). Proposed studies will be executed in collaboration with external investigators from various US institutions, and the direction, approaches and generated results will be discussed with members of the Advisory Group.